Peroxisome proliferator activated receptors (PPARs) belong to the superfamily of transcription factors known as nuclear receptors. This family includes steroid, retinoid and thyroid hormone receptors. Three sub-types of PPARs have been identified in humans, rodents and Xenopus laevis. They are PPARα, PPARβ/δ and PPARγ, each encoded by a different gene and showing different tissue distribution.
The gene encoding for PPARγ is transcribed in humans in three different mRNA isoforms (PPARγ1, PPARγ2 and PPARγ3) through different splicing and promoter usage (Fajas et al., J. Biol. Chem. 1997, vol. 272, p. 18779-18789). The PPARγ1 isoform shows a wide tissular distribution, while PPARγ2 and PPARγ3 are confined to certain tissues: PPARγ2 is expressed only in adipose tissue and PPARγ3 in adipose tissue as well as in macrophages (Fajas et al., FEBS Lett. 1998, vol. 438, p. 55-60).
Differences detected in tissue distribution as well as in the activation profile of the PPARγ isoforms suggest they are involved in a variety of physiological functions playing a central role in glucose homeostasis and lipid metabolism (Vamecq et al., Lancet 1999, vol. 354, p, 141-148). These functions include, for example, lipidic transport in plasma and catabolism of fatty acids, regulation of insulin sensitivity and blood glucose levels, differentiation of macrophages that form atherosclerotic plaques, inflammatory response, carcinogenesis, hyperplasia, and adipocyte differentiation, the latter being the most verified function of the PPARγ (Grimaldi, Prog. Lipid Res. 2001, vol. 40, p. 269-281; Schiller et al., J. Biol. Chem. 2001, vol. 276, p. 14133-14137). Thus, the discovery of these transcription factors has provided new pharmacological targets for the development of useful therapeutic agents for the prevention and treatment of metabolic diseases such as diabetes, obesity and dyslipidaemia.
Non-insulin dependent diabetes mellitus (NIDDM) or type 2 diabetes is characterized by an insulin resistance in peripheral tissues, including muscle, liver, and adipose tissue. Glitazones, selective PPARγ agonist compounds, are drugs that reduce insulin resistance and lower blood glucose levels. Currently two products belonging to this family, rosiglitazone and pioglitazone, have been approved for the treatment of type 2 diabetes in humans.
A great effort has been made in recent years to design new drugs that improve the side effect profile of the first glitazones, show a greater affinity as a PPARγ ligands, and increase their potency in type 2 diabetes. This rational design has yielded structurally diverse compounds that show great potency and selectivity (e.g. farglitazar).
PPARγ agonists have had shortcomings which have so far detracted from their attractiveness, such as liver toxicity (especially troglitazone), weigh gain, edema, heart weight gain (in rodents) and adiposity, as well as modest efficacy in monotherapy for type 2 diabetes. These facts have provided an incentive to develop improved insulin sensitizers.
Compounds totally or partially blocking PPARγ activity have demonstrated to inhibit adipocyte differentiation. Thus, full antagonists constitute an effective treatment for obesity. Moreover, compounds that are partial agonists in addition of being antagonists may be particularly desirable because they are effective in treating not only obesity but also in controlling hyperglycemia. The PPARγ antagonists/partial agonists are therefore effective in treating obesity and other symptoms that generally occur in non-insulin dependent diabetes, such as elevated plasma levels of glucose, tryglicerides, and insulin.
Recently, there have been reports of compounds that are PPARγ antagonists or partial agonists (WO01/30343, WO02/08188, WO2004/020408), which are useful for the treatment of obesity and type 2 diabetes, with reduced side effects (Berger et al., Trends Pharmacol. Sci. 2005, vol. 26, p. 244-51).
Examples of partial agonists in clinical development for diabetes are (−)-halofenate (metaglidasen), FK 614 (Minoura et al., Eur. J. Pharmacol. 2004, vol. 494, p. 273-8), T131 (Li et al., 64th Annu. Meet Sci. Sess. Am. Diabetes Assoc. (June 4-June 8, Orlando) 2004, Abst 659-P), LY818 (Reifel-Miller et al., Diabetes 2003, 52 (Suppl. 1): Abst 614-P) and telmisartan, an angiotensin II blocker approved for the treatment of hypertension, with PPAR partial agonistic activity at concentrations achievable at plasmatic levels during treatment (Kurtz et al., Acta Diabetol. 2005; vol. 42 Suppl 1: S 9-16) which are currently in phase II of clinical development.
In Henkel et al., J. Med. Chem. 1998, vol. 41, p. 5020-5036; Collins et al., J. Med. Chem. 1998, vol. 41, p. 5037-5054; Cobb et al., J. Med. Chem. 1998, vol. 41, p. 5055-5069, WO 94/29285 and in WO 97/31907 de N-(2-benzoylphenyl)-L-tyrosine derivatives are described as being potent and selective PPARγ agonists. Documents WO 03/011814 and WO 03/011834 disclose N-(2-benzoylphenyl)-L-tyrosine derivatives as partial PPARγ agonists. Document U.S. Pat. No. 6,274,608 describes N-(2-benzoylphenyl)-L-tyrosine derivatives as being useful in the treatment and/or prevention of conditions mediated by Retinoid X Receptor (RXR) and the PPAR families.
Obviously, it is of great interest to provide new therapeutic agents that modulate PPARγ.